A central paradox in transforming growth factor beta (TGF-?) biology is how the same growth factor can induce such divergent responses as growth stimulation (i.e., mesenchymal cells) and growth inhibition (i.e., epithelial cells)? Considering the pivotal role TGF-? has in a number of normal and pathological conditions, addressing that issue is fundamental if we hope to develop specific intervention strategies. To that end, we have been investigating the general hypothesis that TGF-? signaling is regulated by the coordinate action of membrane proximal and nuclear TGF-? receptor (TGF-?R) activity. In support of that proposal, we provide evidence that (i) FAK (focal adhesion kinase) has an obligate scaffolding function in profibrotic TGF-? signaling whereby it couples the ligand-activated type I TGF-?R to the p85 subunit of PI3K, the most upstream component regulating non-Smad pathways such as PAK2/c-Abl and Akt/mTOR; and (ii) plasma membrane localized type I and type II TGF-?Rs undergo retrograde trafficking and nuclear import following addition of ligand. In this competing renewal we will extend these concepts using a variety of biochemical, genetic, and morphologic approaches. First, we will determine how FAK regulates non-Smad TGF-? signaling through cell type-specific binding with the type I TGF-?R. As the number of effective therapeutic strategies for organ fibrosis is limited, defining this interaction provides potential approaches to uncouple TGF-?'s fibroproliferative actions. Second, the mechanism and targets of TGF-?R trafficking from the cell surface to the nucleus will be defined. These results extend the paradigm whereby the cellular environment directs distinct TGF-? signaling responses. Moreover, as there is significant activity in developing inhibitors to TGF-? action, nuclear TGF-?R activity might impact the efficacy of these treatments. PUBLIC HEALTH RELEVANCE: TGF-? is a protein which can be either helpful or harmful to human health. While its ability to stimulate cell growth is important for normal wound healing, when unchecked the function of many organs can be disrupted by scar (i.e., fibrosis) formation. Conversely, the growth inhibitory actions of TGF-? are critical in preventing cancer. The proposed studies will identify/characterize targets which direct these different activities and can be used to either increase or decrease the response.